Metabolism of 3-tert-butyl-4-hydroxyanisole by microsomal fractions and isolated rat hepatocytes

S. W. Cummings, G. A S Ansari, F. P. Guengerich, Ghulam Ansari, R. A. Prough

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Abstract

3-tert-Butyl-4-hydroxyanisole is oxidatively metabolized in the presence of rat liver microsomes, reduced nicotinamide adenine dinucleotide phosphate, and oxygen to yield tert-butylhydroquinone, tert-butylquinone, and a polar metabolite(s). In the presence of human and rat liver microsomes or eight purified cytochrome P-450 isozymes reconstituted with NADPH-cytochrome P-450 reductase, this phenolic antioxidant is converted to the oxidoreduction-active metabolite, tert-butylquinone, that can stimulate the NADPH oxidase activities of these preparations by 2- to 7-fold. The rate of formation of each of the metabolites of 3-tert-butyl-4-hydroxyanisole was increased by pretreatment of rats with either 5,6-benzoflavone or phenobarbital. In addition the tert-butylhydroquinone and tert-butylquinone concentrations in solution reached apparent steady-state levels during metabolism; the steady-state concentrations were also increased by various animal pretreatment regimens. Furthermore it was shown that the metabolism of 3-tert-butyl-4-hydroxyanisole yielded material which was covalently bound to protein. In the presence of glutathione the rates of formation of the polar metabolite(s) were enhanced 3- to 4-fold, while covalently bound products were nearly stoichiometrically decreased. The increase in the amount of polar metabolite was due to the formation of a 3-tert-butyl-4-hydroxyanisole-glutathione conjugate. 3-tert-Butyl-4-hydroxyanisole was also oxidatively metabolized by rat lung microsomes to yield the polar metabolite(s) and tert-butylhydroquinone. The polar metabolite(s), tert-butylquinone, and tert-butylhydroquinone were also shown to be formed in isolated hepatocyte suspensions. They could be found as either the free hydroquinone, the sulfate conjugate, the glucuronide conjugate, and polar metabolites, presumedly the 3-tert-butyl-4-hydroxyanisole-glutathione conjugate. The total tert-butylhydroquinone concentration attained a steady-state level in a manner similar to that seen with the microsomal suspensions. In addition 3-tert-butyl-4-hydroxyanisole itself formed sulfate and glucuronide conjugates, the glucuronide being the major product.

Original languageEnglish (US)
Pages (from-to)5617-5624
Number of pages8
JournalCancer Research
Volume45
Issue number11 II
StatePublished - 1985

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Hepatocytes
Glucuronides
Glutathione
Liver Microsomes
Sulfates
Suspensions
beta-Naphthoflavone
NADPH-Ferrihemoprotein Reductase
NADPH Oxidase
Phenobarbital
Microsomes
3-tert-butyl-4-hydroxyanisole
NADP
Cytochrome P-450 Enzyme System
Isoenzymes
Antioxidants
2-tert-butylhydroquinone
Oxygen
Lung
2-tert-butyl-4-quinone

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cummings, S. W., Ansari, G. A. S., Guengerich, F. P., Ansari, G., & Prough, R. A. (1985). Metabolism of 3-tert-butyl-4-hydroxyanisole by microsomal fractions and isolated rat hepatocytes. Cancer Research, 45(11 II), 5617-5624.

Metabolism of 3-tert-butyl-4-hydroxyanisole by microsomal fractions and isolated rat hepatocytes. / Cummings, S. W.; Ansari, G. A S; Guengerich, F. P.; Ansari, Ghulam; Prough, R. A.

In: Cancer Research, Vol. 45, No. 11 II, 1985, p. 5617-5624.

Research output: Contribution to journalArticle

Cummings, SW, Ansari, GAS, Guengerich, FP, Ansari, G & Prough, RA 1985, 'Metabolism of 3-tert-butyl-4-hydroxyanisole by microsomal fractions and isolated rat hepatocytes', Cancer Research, vol. 45, no. 11 II, pp. 5617-5624.
Cummings, S. W. ; Ansari, G. A S ; Guengerich, F. P. ; Ansari, Ghulam ; Prough, R. A. / Metabolism of 3-tert-butyl-4-hydroxyanisole by microsomal fractions and isolated rat hepatocytes. In: Cancer Research. 1985 ; Vol. 45, No. 11 II. pp. 5617-5624.
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abstract = "3-tert-Butyl-4-hydroxyanisole is oxidatively metabolized in the presence of rat liver microsomes, reduced nicotinamide adenine dinucleotide phosphate, and oxygen to yield tert-butylhydroquinone, tert-butylquinone, and a polar metabolite(s). In the presence of human and rat liver microsomes or eight purified cytochrome P-450 isozymes reconstituted with NADPH-cytochrome P-450 reductase, this phenolic antioxidant is converted to the oxidoreduction-active metabolite, tert-butylquinone, that can stimulate the NADPH oxidase activities of these preparations by 2- to 7-fold. The rate of formation of each of the metabolites of 3-tert-butyl-4-hydroxyanisole was increased by pretreatment of rats with either 5,6-benzoflavone or phenobarbital. In addition the tert-butylhydroquinone and tert-butylquinone concentrations in solution reached apparent steady-state levels during metabolism; the steady-state concentrations were also increased by various animal pretreatment regimens. Furthermore it was shown that the metabolism of 3-tert-butyl-4-hydroxyanisole yielded material which was covalently bound to protein. In the presence of glutathione the rates of formation of the polar metabolite(s) were enhanced 3- to 4-fold, while covalently bound products were nearly stoichiometrically decreased. The increase in the amount of polar metabolite was due to the formation of a 3-tert-butyl-4-hydroxyanisole-glutathione conjugate. 3-tert-Butyl-4-hydroxyanisole was also oxidatively metabolized by rat lung microsomes to yield the polar metabolite(s) and tert-butylhydroquinone. The polar metabolite(s), tert-butylquinone, and tert-butylhydroquinone were also shown to be formed in isolated hepatocyte suspensions. They could be found as either the free hydroquinone, the sulfate conjugate, the glucuronide conjugate, and polar metabolites, presumedly the 3-tert-butyl-4-hydroxyanisole-glutathione conjugate. The total tert-butylhydroquinone concentration attained a steady-state level in a manner similar to that seen with the microsomal suspensions. In addition 3-tert-butyl-4-hydroxyanisole itself formed sulfate and glucuronide conjugates, the glucuronide being the major product.",
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AU - Prough, R. A.

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